Submissions for variant NM_000391.4(TPP1):c.851G>T (p.Gly284Val)

gnomAD frequency: 0.00001  dbSNP: rs119455957

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000531153	SCV000628919	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the TPP1 protein (p.Gly284Val). This variant is present in population databases (rs119455957, gnomAD 0.002%). This missense change has been observed in individual(s) with late-infantile neuronal ceroid lipofuscinosis (CLN2) (PMID: 11339651, 12414822, 18684116). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2647). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TPP1 function (PMID: 19038966, 20340139). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763266	SCV000893909	pathogenic	Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000002766	SCV001193869	pathogenic	Neuronal ceroid lipofuscinosis 2	2019-11-11	criteria provided, single submitter	clinical testing	NM_000391.3(TPP1):c.851G>T(G284V) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of this disease. Sources cited for classification include the following: PMID 18684116, 12414822, 11339651 and 20340139. Classification of NM_000391.3(TPP1):c.851G>T(G284V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM	RCV000002766	SCV000022924	pathogenic	Neuronal ceroid lipofuscinosis 2	2008-09-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000002766	SCV000091200	not provided	Neuronal ceroid lipofuscinosis 2		no assertion provided	not provided
Natera, Inc.	RCV000002766	SCV002094848	pathogenic	Neuronal ceroid lipofuscinosis 2	2020-11-16	no assertion criteria provided	clinical testing